Substituted thiadiazoles



Patente d Sept 12, 1944 I v UNITED smras PATENT orrica Richard 0. Roblin, In, and Philip Stanley Winnck, Stamford, Coma, minors to American company, New York, N. '23, a j corporation otlifaine No Drawing. Application new 28. 1940, 1

ScriaiNo. mam

4 Claims. (c1. zen-seas) This invention relates to a new class of chemicompound or by hydrolyzing the corresponding cal compounds, namely p-arylene sulfonamido acyl compound.

' thiadiazoles and more particularly it relates to The p-arylene sulionamido-p-arylene comthe class of compounds which are represented pounds can be prepared by reacting the correy the f w g general formula: 5 sponding sulianilamido thiadiazole with N-acetyl suiianilyl chloride. R Sm-g T2 The amino thiadiazoles used as intermediates in the above processes may be any one of the wherein It represents a nitro, amino, or substituted ammo group such as ammo, wk following isomers, in which the linkages are as n O, monmaldose in no, sodium formalde l follows: -amino-1,2,4 thiadiazole hyde sulfoxylate amino and the like. Ar stands NHi-0=N for a p-arylene or p-arylene sulionamido p-aryli, ene group, X is either hydrogen, a metal or lower L alkyl radical and Ta is thiadiazole or substituted thiadiazole united through a carbon atom of the 3411111110433 iflml thiadiazole ring to the nitrogen atom of the 11-c= sulfonamido group. The substituted thiadiazoles include the compounds in which the hydrogen &

on the carbon atom not attached to the sulionamido group is replaced by a nitro, amino, halo- 2-amino-l,3,4 thiadiazole gen, allcyl, aryl, aralkyl, cycloaliphatic, alkoxy, NHFC=N hydroxy, carboxylic, sulionic, or similar radicals A and also acid or metal salts when the above radical is}. salt-forming constituent.

The present invention is not limited to any particular process of preparing the new compounds. We have found, however, that good tmadiazole yields of the compounds in which R is a Ditto radical are obtained by reacting the aminothiadiazole with a p-nitrobenzene sulfonyl chloride I'd:

suspended in a suitable organic solvent such as pyridine, dioxane or the like, at a slightly eleminim-L23 tmad-imle vated temperature and after completion of the E' reaction neutralizing with an alkali metal hydroxide to form a, precipitate of the p-nitroben- 1 zene sulfonamido thiadiazole which can then be purified by crystallization from a suitable solvent. N=c-NH,

The corresponding p-acylaminobenrene sul- 4o fonamido thiadiazoles are prepared by a similar 1 process when a p-acylaminobenzene sulionyl chloride is employed as one of the reactants in- The hydrogen atom on the 2, 3, 4 and 5 carbon stead of the p-nitrobenzene sulionyl chloride. atoms respectively, may of course be replaced by The p-acetylaminobenzene' sulfonyl chloride is the various substituents as indicated in the genusually employed in the above reaction, due to eral formula above. its being relatively cheap and to the fact that it Many of the compounds of this invention are can easily be hydrolyzed to the p-amino comuseful as therapeutic agents and have been found pound. When, however, .p-acyl compound is to be active against gram negative, intestinal desired as the final product, various other acyl 5o pathogenic organisms such as dysentery bacilli, radicals such as butyryl, benzoyl, nicotinyl, and typhoid and paratyphoid bacilli and the like. the like may be employed instead of the acetyl They are also useful as intermediates in the radical. preparation of other chemical compounds, such The sulianilamido thiadiazoles can either be as for example, azo dyes. prepared by reducing the corresponding nitro The invention will be described in greater detail in connection with the following specific examples which are merely illustrative of the preferred method of preparing certain representative compounds and not intended to limit the scope of the invention. The parts in the examples are by weight except in the case or liquids which are corresp n i parts by volume.

EXAMPLE 1 2- (suljanilamido) -1,3,4 thiadiazole Sixteen and one-half parts (0.163 mol) of 2-amino-1.3,4 thiadiazole was covered with 43 parts of anhydrous pyridine. To the mixture was added 50 parts (0.214 mol) of p-acetyla'minobenzene sulfonyl chloride with vigorous shaking at 50-60 C. The reaction mixture was then heated to 125 C. when the mixture had cooled somewhat it was placed in a Claisen flask and 27.6 parts (0.69 mol) of sodium hydroxide dissolved in 110 parts of .water was added through Emma: 2

Sodium formaldehyde sldforylate derivative The sodium formaldehyde sulfoxylate'derivative of 2(su1fani1amido)-1,3,4 thiadiazole is prepared by reacting it with a slight excess of sodium formaldehyde sulfoxylate in glacial acetic acid and precipitating the product with dry ether. It is readily soluble in water.

Exsmu 3 Sodium salt of 2(sulfaailamido) -1,3,4 thiadiaaole The sodium salt is prepared by adding 2- (sulfanilamido) -1,3,4 thiadiazole to the equivalent amount of sodium hydroxide dissolved in a very small volume of water. The mixture is warmed on a steam bath until solution is complete. Absolute alcohol is then added and the sodium salt is precipitated as a white crystalline material. It is readily soluble in water.

Other alkali metal salts can be prepared in a similar manner by using the appropriate alkaline hydroxide. I

Salts of heavy metals, as for example the copper, gold, lead and iron salts, may be formed by reacting the alkali metal salts in aqueous solution with a suitable soluble salt of the metal desired. The desired product is obtained usually as a p recipitate.

Examm: 4 Mono-aldose derivatives of 2 (sulfanilamido) 4,3,4

. thiadiazole v v The sugar derivatives are prepared by refluxing 2-(sulfanilamido) -1,3,4 thiadiazole with a mono-aldose sugar such as glucose or galactose, in ethanol. The materials gradually go into solution and on cooling the alcoholic solution, the sugar derivative crystallizes out. They are quite soluble in water.

Exams: 5

2- (p-nitrobenzene suljonamido) -1,3,4-thiadiazole One part (0.01 mol) of 2-aminothiadiazole was mixed with 3 parts of anhydrous pyridine and cooled. To the mixture was added 2 parts (0.009 mol) of p-nitrobenzene sulfonyl chloride with thorough stirring. The reaction mixture was heated on a steam bath and then allowed to cool at room temperature. Upon dilution with water the p-nitrobenzene' sulfonamido thiadiazole precipitated and was filtered off. It was recrystallized from nitromethane. The 2-sulfanilamido-1,3,4-thiadiazole described in Example 1 may be obtained by iron reduction of the nitro compound (see Example 7).

Exaurus 2- (p-nitr obenzene sul/(mamido) -5-methul-1,3,4- thiadiazole The 2 (p nitrobenzene sulfonainido) -5- methyl-1,3,4-thiadiazole obtained in the preceding example was added gradually to a hot sus-' pension of 50 parts of iron dust in 200 partsof 95% ethanol containing 2 parts of hydrochloric acid (1:1) The reaction mixture was heated on a steam bath withgood agitation for 8 hours. It was then neutralized with dilute sodium hydroxide and filtered hot. Onaddition of water the crude 2-sulianilamido-5-methyl-1,3,4-thiadiazole separated. It was purified by recrystallization from water.

Exnrrull 2- (p-nitrobenzene suljonamido) -5-phenyl-1,3,4-

thiadiazole To 17.7 parts (0.1 mol) of 2-amino-5-phenyl- 1,3,4-thiadiazole was added 60 parts of anhydrous pyridine. 26.5 parts (0.12 mol) of p nitrobenzene sulfonyl chloride was added to the resulting mixture gradually with stirring. The reaction mixture was then heated on the steam bath for 3 hours. After cooling the 2- (p-nitrobenzene sulfonamido) 5 phenyl 1,3,4-thiadiazole was separated by the addition of ice water.

, EXAMPLE 9 2-suljanilamido-5-phenyl-1,3,4-thiadiazole The nitro compound from the preceding example was added gradually to a hot suspension of 40 parts of iron dust in 250 partsof 95% alcohol containing 2 parts of hydrochloric acid (1:1). The reaction mixture was heated on a in which X is a member of the group consisting of hydrogen and metals prepared for use as a therapeutic. f

2. Compounds represented by the following formula:

in which R represents a sodium formaldehyde sulfoxylate amino radical prepared for use as a I therapeutic.

3. z-sulfanilamido-fi-methyl 1,3,4-thiadlazo prepared for use as a therapeutic.

4. Compounds of the group consisting of those having the following formula:

in which ZN is a radical of the group consisting of NH2, groups reducible thereto, and groups hydrolyzable thereto; and R is taken from the group consisting of alkyl hydrocarbon and phenyl radicals and salts thereof, prepared for use as therapeutic agents.

RICHARD O. ROBLIN, Jn.

PHILIP STANLEY WINN'EK. 

